title: Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer.
abstract: The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy.
authors.affiliation: Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.forename: Su
authors.initials: S
authors.lastname: Qu
authors.forename: Martina
authors.initials: M
authors.lastname: Tesikova
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Alexandr
authors.initials: A
authors.lastname: Kristian
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.forename: Haiying
authors.initials: H
authors.lastname: Kong
authors.forename: Tianzhou
authors.initials: T
authors.lastname: Zhang
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Erkan
authors.initials: E
authors.lastname: Yuca
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Tekedereli
authors.forename: Kivanc
authors.initials: K
authors.lastname: Gorgulu
authors.forename: Neslihan
authors.initials: N
authors.lastname: Alpay
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Håvard E
authors.initials: HE
authors.lastname: Danielsen
authors.forename: Bulent
authors.initials: B
authors.lastname: Ozpolat
authors.forename: Fahri
authors.initials: F
authors.lastname: Saatcioglu
mesh_terms: D000728:Androgens / Q000378:metabolism*; D016923:Cell Death; D002455:Cell Division; D004789:Enzyme Activation; D016193:G1 Phase; D055785:Gene Knockdown Techniques; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000502:physiology*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D007610:Kallikreins; C120801:kallikrein 4